Updated project metadata. Host cell proteins are inevitable contaminants of biopharmaceuticals. Here, we performed detailed analyses of the host cell proteome of moss (Physcomitrella patens) bioreactor supernatants using mass spectrometry and subsequent bioinformatics analysis. Distinguishing between the apparent secretome and intracellular contaminants, a complex extracellular proteolytic network including subtilisin-like proteases, metallo-proteases and aspartic proteases was identified. Further, we confirmed predicted cleavage sites of 40 endogenous signal peptides employing an N-terminomics approach.